1. Field of the Invention
The present invention is directed to pharmaceutical compositions, and primarily to topically applied ophthalmic compositions comprising as the active ingredient one or more compounds having the ability to block potassium channels in the ciliary epithelium, e.g. to inhibit the transport of potassium ions and fluid secretion in epithelia. The pharmaceutical compositions are useful for reducing intraocular pressure in animals of the mammalian species. In another aspect, the present invention is directed to administering such formulations and compositions to animals of the mammalian species (including humans) for reducing intraocular pressure in the eye.
2. Brief Description of the Art
Glaucoma is an optical neuropathy associated with elevated intraocular pressures which are too high for normal function of the eye, and results in irreversible loss of visual function. It is estimated in medical science that glaucoma afflicts approximately 2 percent of the population over the age of forty years, and is therefore a serious health problem. Ocular hypertension, i.e. the condition of elevated intraocular pressure, which has not yet caused irreversible damage, is believed to represent the earliest phase of glaucoma. Many therapeutic agents have been devised and discovered in the prior art for the treatment or amelioration of glaucoma and of the condition of increased intraocular pressure which precedes glaucoma.
Primary open angle glaucoma (POAG) is associated with a rise in intraocular pressure (IOP). This increase in IOP is believed to contribute to the loss of optic nerve function which ultimately leads to blindness. Reduction of IOP is therefore a crucial component in the management of POAG.
In principle, IOP can be reduced by inhibiting aqueous humor inflow or conversely by stimulating aqueous outflow. Aqueous humor inflow is mediated by ion transport across the ciliary epithelium. The above secretion of aqueous humor produced by the ciliary epithelium is then drained from the eye (aqueous outflow) via the trabecular meshwork into Schlemm's canal.
Because ion transport mediates secretion of aqueous humor, blocking or modulating the relevant ion channels or carriers will consequently inhibit or reduce aqueous formation and thus lower IOP. On the other hand, since the trabecular meshwork (TM) is a major obstacle (resistance pathway) to aqueous outflow, reducing its resistance to the passage of fluid should enhance outflow and lower IOP. Thus, by reducing the volume or size of TM cells it should be possible to enhance outflow by lowering the resistance to the passage of ocular fluid. Cell volume/size is determined by a balance between ion uptake and efflux mechanisms. Therefore, it follows that reducing TM cell volume can be accomplished by either stimulating the ion efflux or inhibiting the ion uptake mechanisms in this cell type.
The drugs currently utilized in the treatment of glaucoma include miotics (e.g., pilocarpine, carbachol, and acetylcholinesterase inhibitors), sympathomimetrics (e.g., epinephrine and dipivalylepinephrine), beta-blockers (e.g., betaxolol, levobunolol and timolol), alpha-2 agonists (e.g., para-amino clonidine) and carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide and ethoxzolamide). Miotics and sympathomimetics are believed to lower intraocular pressure by increasing the outflow of aqueous humor, while beta-blockers, alpha-2 agonists and carbonic anhydrase inhibitors are believed to lower intraocular pressure by decreasing the formation of aqueous humor. All five types of drugs have potential side effects. Miotics, such as pilocarpine, can cause blurring of vision and other visual side effects which may either decrease patient compliance or require termination of miotic drug therapy. Carbonic anhydrase inhibitors can also cause serious side effects which affect patient compliance and/or necessitate withdrawal of the drug therapy. At least one beta-blocker, timolol, has increasingly become associated with serious pulmonary side effects attributable to its effect on beta-2 receptors in pulmonary tissue.
As a result additional antiglaucoma drugs are being developed, e.g., prostaglandin derivatives, muscarinic antagonists, etc.
In light of the foregoing circumstances, it is clear that a need exists for new, more potent antiglaucoma compositions which avoid or reduce the above-cited side effects and enhance patient compliance, since the foregoing and other anti-glaucoma and ocular hypotensive compounds and agents of the prior art do not provide a treatment or cure for glaucoma and ocular hypertension which is satisfactory in all respects. Therefore, the pharmacological and related arts and sciences continue searching for additional and better anti-glaucoma and ocular hypotensive agents.
Chloride channel blockers such as 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) have been shown to inhibit Cl-transport and fluid secretion/absorption in rat intestine. (See for example, Acta Physiol Scand: No. 149,1993: pp. 365-376, Fryklund et al., "The effects of potassium transport inhibitors on intestinal fluid and ion transport in vivo and in vitro".)
The use of chloride-channel blockers for reducing the intraocular pressure in the eye of a mammal is disclosed and claimed in U.S. patent application Ser. No. 346,660, which was filed on Nov. 30, 1994 in the names of Adorante et al, which is herein incorporated by reference in its entirety.
In addition, PCT Patent WO 89/10757 discloses the use of potassium channel openers for treating glaucoma.